SCHIZOPHRENIA/METHAMPHETAMINE
| NEWER ANTIPSYCHOTIC DRUGS AND SCHIZOPHRENIA —John M. Kane, MD, Professor of Psychiatry, Neurology,
and Neurosciences, Albert Einstein College of Medicine, and Chairman, Department of Psychiatry, The Zucker
Hillside Hospital, Glen Oaks, NY
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| Introduction: pharmacologic treatment alone not enough to treat schizophrenia and to help patient remain functional;
treatment regimen must also include psychosocial treatments, vocational rehabilitation, and supportive
housing; cognitive dysfunction and negative symptoms account for more psychosocial and functional disability
than do positive symptoms; treatment adherence especially troublesome in schizophrenia, where insight may be
lacking and cognitive dysfunction present; in addition, enormous social stigma associated with schizophrenia and
medication side effects contribute to noncompliance
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| Nonresponse: how long to continue trial with antipsychotic drug before deciding patient not responding? 50 experts
in schizophrenia surveyed, said initial trial of medication should last 2.5 to 5.5 wk (“that’s a pretty big
spread”); same interval for second antipsychotic medication; meta-analysis showed most improvement occurs
within first 4 wk, with largest percentage of that improvement within first week; when trial extended to 52 wk,
reduction in symptoms from beginning of trial through wk 4 greater than reduction from wk 5 through wk 51
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 | What to do when first medication has not worked: experts disagreed; no good data on how many drugs to try before
using clozapine
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| Positive and Negative Symptom Scale (PANSS): may not be adequate measure of response to medication; ultimate
goal of treatment is remission, “but we don’t really think about remission in schizophrenia”; recent study proposed
remission criteria
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| First episode of psychosis: tempting to patient and therapist to discontinue medications after 1 yr with no symptoms,
but risk for relapse high; in study, 5 yr after first episode, relapse rate 82%; patients who discontinued medication
5 times more likely to relapse; speaker recommends continued treatment in first-episode patients
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| Recovery: how to define recovery in schizophrenia? one group proposed that recovery criteria must be met in each
of 4 domains for at least 2 yr; domains include symptom remission, appropriate role function, ability to perform
day-to-day living tasks without supervision, and social interaction; in study, only 14% of first-episode patients met
these criteria at end of 5 yr; relapse interferes with recovery (“if you relapse, the clock starts all over again, and it
takes you another 2 yr to meet the recovery criteria”)
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| Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): randomized controlled trial sponsored
by National Institutes of Mental Health (NIMH) to compare efficacy and tolerability of typical and atypical
antipsychotic drugs in treatment of schizophrenia; patients with first episode of schizophrenia not eligible, but few
other exclusion criteria; any patient with tardive dyskinesia at baseline not eligible for randomization to perphenazine;
primary outcome measure was all-cause treatment discontinuation; dose equivalence controversial (no good
data available) and unknown if selected dose equivalents played role in results of trial; 74% of patients who entered
trial discontinued first medication; <50% got to maximum dose; discontinuation least (64%) with olanzapine;
>50% of all patients discontinued by 6 mo
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| Adverse effects: tardive dyskinesia—incidence with conventional antipsychotic medications ≈5% per year in first
5 yr; diminishes over time; risk “considerably lower” with second-generation antipsychotic medications; metabolic
side effects—in CATIE, more patients discontinued olanzapine than other medications due to weight gain (≈2 lb/
mo); in study of drug-naïve adolescents taking antipsychotic medications for first time, after 12 wk, 81% of patients
on olanzapine gained >7% of their body weight, 67% on quetiapine or risperidone, and 50% on aripiprazole;
other adverse events in adolescents included hypercholesterolemia and insulin resistance
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| Augmentation: valproate—if patient does not respond to antipsychotic medication, popular to add valproate, but no
data to support that practice; although some studies found positive effect of adding valproate to antipsychotic medication,
large meta-analysis showed no significant effect; antidepressants—found to have positive effect on negative
symptoms and depression; glutamatergic drugs—no significant effect on negative or positive symptoms; lithium—
shown to have some positive effect in patients who are poor or partial responders to antipsychotic medications; electroconvulsive
therapy (ECT)—effective as monotherapy in people with schizophrenia, but only limited data available
to support its use as augmentation to antipsychotic medications; speaker’s study of ECT in clozapine
nonresponders just being completed, results not yet available
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| Compliance: problematic; prescription-refill database shows linear relationship between length of time without
medication and rate of hospitalization, starting with gap as short as 1 to 10 days; many clinicians reluctant to accept
that patients may not be following medication recommendations (in survey, experts estimated average rate of compliance
among all patients with schizophrenia 28%, but 43% among their own patients); partial compliance leads to
relapse and rehospitalization; speaker posits that second-generation antipsychotic medications have advantage in
producing fewer neurologic side effects, particularly tardive dyskinesia, and may have advantages in improving relapse
rates and negative symptoms; these advantages may be greater in first-episode patients; all psychiatric caregivers
should learn to know and assess metabolic side effects of all antipsychotics
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| METHAMPHETAMINE USE AND ABUSE —Carson R. Harris, MD, Associate Professor of Emergency Medicine,
University of Minnesota Minneapolis Medical School, and Director, Clinical Toxicology Service, Department of
Emergency Medicine, Regions Hospital, St. Paul, MN
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| Introduction: epidemic abuse of methamphetamine in United States began in 1950s, and its distribution and use restricted
by several acts of legislation since then; currently used as “club drug” at raves (all-night parties during
which extensive and indiscriminate use of recreational drugs prevails); street names include crank, crystal, glass,
ice, and crystal meth
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| Drug Abuse Warning Network (DAWN) report: number of emergency department (ED) visits that involve
methamphetamine rising rapidly; 58% of law enforcement agencies polled said that methamphetamine their biggest
drug problem; methamphetamine use greatest in Midwest and Northwest, but use increasing in all areas of
United States; women comprise 38% of people using methamphetamine, one of highest percentages for any drug of
abuse
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| Treatment for methamphetamine abuse: treatment “pretty lacking”; recidivism rate 90%; reported that some
people go through treatment program 12 or 13 times in trying to “kick” habit
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| Methamphetamine laboratories: number of people in United States manufacturing their own methamphetamine
has dropped, but methamphetamine still being smuggled in from Mexico
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| ED epidemiology: in speaker’s facility, most patients 18 to 34 yr of age; 10% to 12% of patients <17 yr of age;
many high school students, especially girls, use methamphetamine to suppress appetite
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| American Indian reservations: seeing increase in use of methamphetamine; plays big role in crime on reservations
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| Methamphetamine marketing: “there’s some science to it”; most sellers try to sell at least one-eighth ounce
(called “an 8 ball”) for $150 to $280 (in general, price indicates purity); one 8 ball enough to get 15 people high;
“glass” or “ice” typically sold for twice as much as 8 ball; cheaper than cocaine and high lasts much longer (≥24 hr)
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| Dose and routes of administration: when used for “medicinal” purposes, dose 10 to 40 mg/day; as recreational
drug, 100 to 1000 mg/day, and up to 5000 mg/day during binge; purity of street methamphetamine now 80% to
90%, with increase seen in complications, side effects, and toxicity (toxic dose 25 mg/kg); methamphetamine
available as powder, capsule, rock, or pill; can be swallowed, snorted, smoked (probably most common route of administration),
or administered intravenously (IV); rock form often indistinguishable from cocaine
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| “Body stuffers” and “body packers”: people insert methamphetamine in various body cavities to hide it from
law enforcement or to transport it; “body stuffers” swallow packets of methamphetamine indiscriminately; “body
packers” may swallow packets or insert them into rectum or vagina, but do it with more forethought so packets can
be retrieved more readily
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| Pharmacology: sympathomimetic drug that causes much central nervous system stimulation; causes release of catecholamines
and blocks their reuptake; can also act like false neurotransmitter, affecting catecholamine receptors;
net effect is increase of neurotransmitter in synapse, leading to stereotypical behavior, euphoria, increased libido,
increased motor activity, decreased fatigue, and in some cases, schizophrenia-like psychosis; methamphetamine
readily absorbed across mucous membranes of gastrointestinal tract, nasopharynx, and tracheobronchial tree; peak
plasma levels occur in 1 to 3 hr; half-life long, and effects can last >24 hr
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| Toxicity: methamphetamine affects “just about every organ in your body”; causes release of dopamine in certain
parts of brain, resulting in “rush”; may cause acute and chronic psychosis, most commonly paranoid psychosis;
can cause stroke, including ischemic stroke, bleeding in brain, and seizures; if seizure accompanied by fever and
cardiac arrest occurs, cardiopulmonary resuscitation rarely successful; also, if fever extremely high (has been recorded
as high as 108°F), cardiac resuscitation rarely successful
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| Cardiovascular toxicity: includes elevated blood pressure and heart rate; other problems include myocardial infarction
and angina; long-term users can develop cardiomyopathy; heart failure, dysrhythmia, myocardial ischemia,
myocardial rupture, and myocardial fibrosis reported; treatment—benzodiazepines usually effective; speaker
discourages use of β-blockers because they do not block α receptors; “if you do use a β-blocker, try something
that’s short-acting; try esmolol”; if IV esmolol does not work, it can be turned off and benzodiazepine started
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| Pulmonary toxicity: barotrauma, including pneumomediastinum and pneumothorax; bronchitis; long-term users often
develop pulmonary problems, eg, infections, bronchitis, and chronic obstructive pulmonary disease, later on
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| Renal and hepatic toxicity: renal failure becoming more frequent and often irreversible, requiring hemodialysis;
hepatitis always risk, especially for IV users
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| Fetal toxicity: controversial whether methamphetamine causes congenital anomalies; extreme irritability most common
ED presentation in infants; other early effects include fetal death, premature delivery, and baby being small
for gestational age; late effects include learning disabilities and poor social adjustment; children of methamphetamine
users often subject to neglect and abuse
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| Other toxicity: skin problems include formication, skin abscesses, cellulitis; “meth mouth” due to chronic abuse
and neglect of oral hygiene
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| Acute psychologic effects: methamphetamine increases confidence, alertness, mood, sex drive, energy, and talkativeness;
can cause panic reactions, hallucinations, and paranoid psychosis
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| “Tweaking”: dangerous phase for health care providers; after patient has experienced initial high, starts to binge in
attempt to repeat it; may binge for 3 to 15 days, “and then at some point, nothing works for him; he doesn’t have any
more meth, and then he starts to crash”; patient becomes paranoid and aggressive, may become very violent; speaker’s
institution treats with “cocktail” of haloperidol (Haldol, 5 mg), lorazepam (Ativan, 2 mg), and benztropine (Cogentin,
1 mg) or diphenhydramine (Benadryl, 25 to 50 mg), but other combinations can be used
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| Methamphetamine withdrawal: usually not life-threatening; may be manifested by depression, fatigue, anxiety,
anergia, paranoia, cognitive impairment, agitation, and/or confusion; duration 2 days to 2 wk; no pharmacotherapy
available; patient likely to harm self or others should be hospitalized; others can be sent home if someone there
willing to help them
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| Children exposed to methamphetamine laboratories: can be harmed by substances used to make methamphetamine;
80% to 90% have positive urine screens for methamphetamine
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Educational Objectives
| The goal of this program is to educate the listener about the use of newer antipsychotic medications in treating schizophrenia
and about the physical and psychologic effects of methamphetamine abuse. After hearing and assimilating
this program, the clinician will be better able to:
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| 1. Explain why people with schizophrenia are often not compliant with treatment regimens.
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| 2. Compare the efficacy and safety of older and newer antipsychotic medications.
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| 3. Discuss the epidemiology of methamphetamine abuse in the United States.
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| 4. Describe the pharmacology and toxicity of methamphetamine.
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| 5. Recommend a rehabilitation program for methamphetamine users.
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Discussed on This Program
Benztropine mesylate [Cogentin]
Clozapine [Clozaril, Fazalco]
Diphenhydramine hydrochloride [Benadryl, others]
Esmolol hydrochloride [Brevibloc]
Haloperidol [Haldol]
Lithium [Eskalith, Lithobid, Lithonate, Lithotabs]
Lorazepam [Ativan, Lorazepam Intensol]
Olanzapine {Zyprexa]
Perphenazine [Trilafon]
Quetiapine fumarate [Seroquel]
Risperidone [Risperdal]
Valproic acid [Depacon, Depakene, Depakote, Depakote ER]
Ziprasidone hydrochloride [Geodon]
Suggested Reading
Agid O et al: Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry
60:1228, 2003; Andreasen NC Kane JM et al: Remission in schizophrenia: proposed criteria and rationale
for consensus. Am J Psychiatry 162:441, 2005; Barr AM et al: The need for speed: an update on methamphetamine
addiction. J Psychiatry Neurosci 31:301, 2006; Correll CU, Kane JM et al: Metabolic syndrome and the risk of
coronary heart disease in 367 patients treated with second-generation antipsychotic drugs. J Clin Psychiatr 67:575,
2006; Gonzales R et al: Hepatitis C virus infection among methamphetamine-dependent individuals in outpatient
treatment. J Subst Abuse Treat 31:195, 2006; Johnson BA et al: Effects of topiramate on methamphetamine-induced
changes in attentional and perceptual-motor skills of cognition in recently abstinent methamphetamine-dependent
individuals. Prog Neuropsychopharmacol Biol Psychiatry Sep 15, 2006; Kane JM, Malhotra A: The future
of pharmacotherapy for schizophrenia. World Psychiatry 2:81, 2003; Kane JM: Review of treatments that can ameliorate
nonadherence in patients with schizophrenia. J Clin Psychiatry 67(Suppl 5):9, 2006; Kane JM: Strategies for
improving compliance in treatment of schizophrenia by using a long-acting formulation of an antipsychotic: clinical
studies. J Clin Psychiatry 64(Suppl 16):34, 2003; Keith SJ, Kane JM: Partial compliance and patient consequences
in schizophrenia: our patients can do better. J Clin Psychiatry 64:1308, 2003; Leucht S, Kane JM et al:
What does the PANSS mean? Schizophr Res 79:231, 2005; Liberman RP, Kopelowicz A: Recovery from
schizophrenia: a concept in search of research. Psychiatr Serv 56:735, 2005; Lieberman JA et al: Clinical Antipsychotic
Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients
with chronic schizophrenia. N Engl J Med 353:1209, 2005; Ling W et al: Management of methamphetamine abuse
and dependence. Curr Psychiatry Rep 8:345, 2006; Marder SR, Kane JM et al: Clinical guidelines: Dosing and
switching strategies for long-acting risperidone. J Clin Psychiatry 64(Suppl 16):41, 2003; McKetin R et al: The
prevalence of psychotic symptoms among methamphetamine users. Addiction 101:1473, 2006; Mendelson J et al:
Human pharmacology of the methamphetamine stereoisomers. Clin Pharmacol Ther. 80:403, 2006; Miller MA,
Coon TP: Re: Delayed ischemic stroke associated with methamphetamine use. J Emerg Med 31:305, 2006; Robinson
D et al: Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder.
Arch Gen Psychiatry 56:241, 1999; Robinson DG et al: Symptomatic and functional recovery from a first
episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 161:473, 2004; Robinson DG, Kane JM et
al: Pharmacological treatments for first-episode schizophrenia. Schizophr Bull 31:705, 2005; Romanelli F, Smith
KM: Clinical effects and management of methamphetamine abuse. Pharmacotherapy 26:1148, 2006; Stroup TS
et al: The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)
project: schizophrenia trial design and protocol development. Schizophr Bull 29:15, 2003.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
Dr. Kane disclosed that he has been a speaker for Abbott, Eli Lilly & Co., and Pfizer, and has consulted for BMS and
Janssen.
Dr. Kane was recorded at Inspirational Insights from Incandescent Illuminati, held March 10-11, 2006, in Madison,
WI, and sponsored by the University of Wisconsin School of Medicine and Public Health and the Madison Institute
of Medicine, Inc. Dr. Harris was recorded at The 6th Annual Psychiatry Update, held April 28, 2006, in Minneapolis,
MN, and sponsored by HealthPartners Medical Group and Clinics and HealthPartners Institute for Medical Education.
The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of
this program.
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